Structure-aided optimization of 3-O-β-chacotriosyl ursolic acid as novel H5N1 entry inhibitors with high selective index.
Identifieur interne : 000A87 ( Main/Exploration ); précédent : 000A86; suivant : 000A88Structure-aided optimization of 3-O-β-chacotriosyl ursolic acid as novel H5N1 entry inhibitors with high selective index.
Auteurs : Yixian Liao [République populaire de Chine] ; Lizhu Chen [République populaire de Chine] ; Sumei Li [République populaire de Chine] ; Zi-Ning Cui [République populaire de Chine] ; Zhiwei Lei [République populaire de Chine] ; Hui Li [République populaire de Chine] ; Shuwen Liu [République populaire de Chine] ; Gaopeng Song [République populaire de Chine]Source :
- Bioorganic & medicinal chemistry [ 1464-3391 ] ; 2019.
Abstract
Currently, entry inhibitors contribute immensely in developing a new generation of anti-influenza virus drugs. Our earlier studies have identified that 3-O-β-chacotriosyl ursolic acid (1) could inhibit H5N1 pseudovirus by targeting hemagglutinin (HA). In the present study, a series of C-28 modified pentacyclic triterpene saponins via conjugation with a series of amide derivatives were synthesized and their antiviral activities against influenza A/Duck/Guangdong/99 virus (H5N1) in MDCK cells were evaluated. The SARs analysis of these compounds revealed that introduction of certain amide structures at the 17-COOH of ursolic acid could significantly enhance both their antiviral activity and selective index. This study indicated that the attachment of the methoxy group or Cl atom to the phenyl ring at the ortho- or para-position was crucial to improve inhibitory activity. Mechanism studies demonstrated that these title triterpenoids could bind tightly to the viral envelope HA to block the attachment of viruses to host cells, which was consistent with docking studies.
DOI: 10.1016/j.bmc.2019.07.028
PubMed: 31350154
Affiliations:
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State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China; State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Chen, Lizhu" sort="Chen, Lizhu" uniqKey="Chen L" first="Lizhu" last="Chen">Lizhu Chen</name><affiliation wicri:level="1"><nlm:affiliation>School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Li, Sumei" sort="Li, Sumei" uniqKey="Li S" first="Sumei" last="Li">Sumei Li</name><affiliation wicri:level="1"><nlm:affiliation>Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou 510632, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou 510632</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Cui, Zi Ning" sort="Cui, Zi Ning" uniqKey="Cui Z" first="Zi-Ning" last="Cui">Zi-Ning Cui</name><affiliation wicri:level="1"><nlm:affiliation>State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Lei, Zhiwei" sort="Lei, Zhiwei" uniqKey="Lei Z" first="Zhiwei" last="Lei">Zhiwei Lei</name><affiliation wicri:level="1"><nlm:affiliation>Guizhou Tea Reasearch Institute, Guizhou Academy of Agricultural Science, Guiyang, Guizhou 550006, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guizhou Tea Reasearch Institute, Guizhou Academy of Agricultural Science, Guiyang, Guizhou 550006</wicri:regionArea><wicri:noRegion>Guizhou 550006</wicri:noRegion></affiliation></author><author><name sortKey="Li, Hui" sort="Li, Hui" uniqKey="Li H" first="Hui" last="Li">Hui Li</name><affiliation wicri:level="1"><nlm:affiliation>College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Materials and Energy, South China Agricultural University, Guangzhou 510642</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Liu, Shuwen" sort="Liu, Shuwen" uniqKey="Liu S" first="Shuwen" last="Liu">Shuwen Liu</name><affiliation wicri:level="1"><nlm:affiliation>School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: liusw@smu.edu.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Song, Gaopeng" sort="Song, Gaopeng" uniqKey="Song G" first="Gaopeng" last="Song">Gaopeng Song</name><affiliation wicri:level="1"><nlm:affiliation>College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China. Electronic address: songgp1021@scau.edu.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Materials and Energy, South China Agricultural University, Guangzhou 510642</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author></analytic><series><title level="j">Bioorganic & medicinal chemistry</title><idno type="eISSN">1464-3391</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Currently, entry inhibitors contribute immensely in developing a new generation of anti-influenza virus drugs. Our earlier studies have identified that 3-O-β-chacotriosyl ursolic acid (1) could inhibit H5N1 pseudovirus by targeting hemagglutinin (HA). In the present study, a series of C-28 modified pentacyclic triterpene saponins via conjugation with a series of amide derivatives were synthesized and their antiviral activities against influenza A/Duck/Guangdong/99 virus (H5N1) in MDCK cells were evaluated. The SARs analysis of these compounds revealed that introduction of certain amide structures at the 17-COOH of ursolic acid could significantly enhance both their antiviral activity and selective index. This study indicated that the attachment of the methoxy group or Cl atom to the phenyl ring at the ortho- or para-position was crucial to improve inhibitory activity. Mechanism studies demonstrated that these title triterpenoids could bind tightly to the viral envelope HA to block the attachment of viruses to host cells, which was consistent with docking studies.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country><region><li>Guangdong</li></region><settlement><li>Jiangmen</li></settlement></list><tree><country name="République populaire de Chine"><region name="Guangdong"><name sortKey="Liao, Yixian" sort="Liao, Yixian" uniqKey="Liao Y" first="Yixian" last="Liao">Yixian Liao</name></region><name sortKey="Chen, Lizhu" sort="Chen, Lizhu" uniqKey="Chen L" first="Lizhu" last="Chen">Lizhu Chen</name><name sortKey="Cui, Zi Ning" sort="Cui, Zi Ning" uniqKey="Cui Z" first="Zi-Ning" last="Cui">Zi-Ning Cui</name><name sortKey="Lei, Zhiwei" sort="Lei, Zhiwei" uniqKey="Lei Z" first="Zhiwei" last="Lei">Zhiwei Lei</name><name sortKey="Li, Hui" sort="Li, Hui" uniqKey="Li H" first="Hui" last="Li">Hui Li</name><name sortKey="Li, Sumei" sort="Li, Sumei" uniqKey="Li S" first="Sumei" last="Li">Sumei Li</name><name sortKey="Liu, Shuwen" sort="Liu, Shuwen" uniqKey="Liu S" first="Shuwen" last="Liu">Shuwen Liu</name><name sortKey="Song, Gaopeng" sort="Song, Gaopeng" uniqKey="Song G" first="Gaopeng" last="Song">Gaopeng Song</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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